Rapidly disintegrating gelatinous coated tablets

ABSTRACT

The present invention relates to an improved gelatinous coated dosage form having two end regions coated with gelatinous materials and an exposed circumferential band. Openings are provided in at least the exposed band to reveal the core material. The invention also relates to methods for manufacturing such gelatinous coated dosage forms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of co-pending applicationhaving U.S. Ser. No. 10/756,528, filed on Jan. 13, 2004.

The present invention relates to a dosage form comprising a tablet corehaving two ends. The tablet core, preferably in compressed form, isprovided with a polymeric subcoating over its exterior surface. Further,the dosage form includes gelatinous coatings over both ends. Thegelatinous endcaps are provided on opposing ends of the elongated tabletcore or opposing sides of a round tablet core so that they do not meetand form a circumferential gap or band through which the subcoating isvisible. Openings are provided in the dosage form that extend throughthe subcoat to the exterior surface of the elongated tablet or roundtablet core. The openings are preferably provided only in the exposedgap of the subcoatings.

BACKGROUND OF THE INVENTION

Capsules have long been recognized as a preferred dosage form for theoral delivery of active ingredients, which may be in the form of powder,liquid or granules of different compositions, for delivery to thegastro-intestinal tract of a human. Advantages of capsules as a dosageform include the variety of shapes and color combinations (includingdifferent colored caps and bodies), enhancing their uniqueidentification, their glossy elegant appearance, and their easyswallowability. One type of commonly used capsule is a two-piece hardshell capsule, typically made from gelatin, starch, or cellulosederivatives. The hard shell capsule typically comprises a longer bodyhaving an outside diameter, and a relatively shorter cap having aninside diameter that will just fit over the outside diameter of thebody. The cap fits snugly over the body, creating an overlapping portionof the capsule.

In view of the tamperability of old-fashioned capsules made with hardshell capsule halves of different diameters which can be taken apart,steps have been taken since the 1980s, to manufacture capsule shellswhich, once assembled, cannot be disassembled without their destruction.One such example is the Capsugel CONI-SNAP® capsule, which has groovesthat lock the cap and body together after the capsule has been filled.Another such example is the Parke-Davis KAPSEAL® capsule, in which thebody and cap are sealed together using a band of gelatin. Although thesealing or banding of capsule shell halves has, in a large part, proveneffective to at least make tampering evident to the consumer, somecompanies have preferred to manufacture solid dosage forms havingdensely compacted cores to further reduce the possibility of tampering.

One of the first types of film-coated elongated compressed tablets wasreferred to as a “caplet”. The caplet form offered enhancedswallowability over uncoated tablets due to its elongated shape andfilm-coated surface, similar to that of the capsule. It did not,however, enable the multi-colored glossy surface appearance of acapsule. While caplets are still popular today, the next generation ofdosage forms, which offered all of these advantages of the capsule,comprised densely compacted cores that were coated with gelatin orsimilar glossy materials, typically in two parts having differentcolors. U.S. Pat. Nos. 5,089,270; 5,213,738; 4,820,524; 4,867,983 and4,966,771 represent different approaches to providing a capsule-shapedproduct in the form of an elongated tablet having a coating, whichprovides the appearance and, therefore, the consumer acceptability ofthe previously popular capsule.

U.S. Pat. Nos. 5,415,868 and 5,317,849 disclose different manners bywhich either hard shell capsule halves can be shrink-wrapped onto atablet (the '868 patent) or a tablet core covered at opposite ends witha soft gelatin capsule shell half and subsequently dried to simulate acapsule-like medicament (the '849 patent). U.S. Pat. No. 5,464,631suggests that studies have also shown the functional importance toconsumers of providing a capsule-appearing solid dosage form, which ismulti-colored. The utilization of two colors functionally identifies thetype of medication as well as provides a capsule-appearing product witha psychologically perceived medicinal efficacy. Aesthetically, also,consumers apparently prefer the attractive appearance of multi-coloredcapsules to single colored capsules.

Thus, there has been a rush by the pharmaceutical industry to provideover-the-counter gelatinous coated dosage forms which simulate theappearance of capsules and which have a variety of multiple colors whichidentify the type of medication provided so that the consumer canreadily identify, for example, if the product is a particular type ofanalgesic or whether it includes antihistamines or other activeingredients in combination with analgesics. Such solid dosage forms havepreferably been in the shape of an elongated tablet, and are identifiedas gelcaps when a solid elongated core is covered with a gelatinouscovering or geltabs where the core is in the shape of a round tabletwith a gelatinous coating.

The present invention furthers these earlier advances by producing animproved gelcap or geltab having faster disintegration and/ordissolution times relative to the commercially available gelatinouscoated products.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an enlarged isometric view of a compressed core in the form ofan elongated tablet having a generally cylindrical shape, called a“gelcap core”.

FIG. 2 is an enlarged isometric view of an intermediate dosage form.

FIG. 3 is a final dosage form of the present invention.

DETAILED DESCRIPTION OF INVENTION

As used herein, the term “dosage form” applies to any solid object,semi-solid, or liquid composition designed to contain a specificpre-determined amount (dose) of a certain ingredient, for example anactive ingredient as defined below. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery, or subcutaneous implants, or other implanted drugdelivery systems; or compositions for delivering minerals, vitamins andother nutraceuticals, oral care agents, flavorants, and the like.Preferably the dosage forms of the present invention are considered tobe solid, however they may contain liquid or semi-solid components. In aparticularly preferred embodiment, the dosage form is an orallyadministered system for delivering a pharmaceutical active ingredient tothe gastro-intestinal tract of a human. In another preferred embodiment,the dosage form is an orally administered “placebo” system containingpharmaceutically inactive ingredients, and the dosage form is designedto have the same appearance as a particular pharmaceutically activedosage form, such as may be used for control purposes in clinicalstudies to test, for example, the safety and efficacy of a particularpharmaceutically active ingredient.

As used herein the term “tablet” refers to a solid form prepared bycompaction of powders on a tablet press, as well known in thepharmaceutical arts. Tablets can be made in a variety of shapes,including round, or elongated, such as flattened ovoid or cylindricalshapes. As used herein, a “gelcap core” refers to one type of elongated,generally cylindrical or capsule-shaped tablet having straight orslightly bowed sides, and a generally circular cross-section, and havinga length to diameter ratio from about 2 to about 5, e.g. from about 2.5to about 3.5, say about 3.

A caplet is one type of elongated tablet covered by a film coating.There is shown in FIG. 1 a core 10 in the shape of an elongated tablethaving two ends 12 at opposing sides of a longitudinal axis. A bellyband14 occurs along the longitudinal circumference where the tablet is incontact with the die walls during compaction.

The core can have any number of pharmaceutically acceptable tabletshapes. Tablet is meant to encompass shaped compacted dosage forms inthe broadest sense. An elongated tablet is a type of tablet having anelongated shape. One type of gelcap core shown in FIG. 1 has a generallycircular cross section that generally tapers from the mid-section to atip or end region. For purposes of this application, the longitudinalaxis passes through the center of both ends of the gelcap core.

The core (or substrate) may be any solid or semi-solid form. The coremay prepared by any suitable method, for example the core be acompressed dosage form, or may be molded. As used herein, “substrate”refers to a surface or underlying support, upon which another substanceresides or acts, and “core” refers to a material that is at leastpartially enveloped or surrounded by another material. For the purposesof the present invention, the terms may be used interchangeably: i.e.the term “core” may also be used to refer to a “substrate.” Preferably,the core comprises a solid, for example, the core may be a compressed ormolded tablet, hard or soft capsule, suppository, or a confectioneryform such as a lozenge, nougat, caramel, fondant, or fat basedcomposition. In certain other embodiments, the core may be in the formof a semi-solid or a liquid in the finished dosage form.

In one embodiment, the core has one or more major faces. The core may bein a variety of different shapes. For example, in one embodiment thecore may be in the shape of a truncated cone. In other embodiments thecore may be shaped as a polyhedron, such as a cube, pyramid, prism, orthe like; or may have the geometry of a space figure with some non-flatfaces, such as a cone, cylinder, sphere, torus, or the like. Exemplarycore shapes that may be employed include tablet shapes formed fromcompression tooling shapes described by “The Elizabeth Companies TabletDesign Training Manual” (Elizabeth Carbide Die Co., Inc., p.7(McKeesport, Pa.) (incorporated herein by reference) as follows (thetablet shape corresponds inversely to the shape of the compressiontooling):

-   -   Shallow Concave.    -   Standard Concave.    -   Deep Concave.    -   Extra Deep Concave.    -   Modified Ball Concave.    -   Standard Concave Bisect.    -   Standard Concave Double Bisect.    -   Standard Concave European Bisect.    -   Standard Concave Partial Bisect.    -   Double Radius.    -   Bevel & Concave.    -   Flat Plain.    -   Flat-Faced-Beveled Edge (F.F.B.E.).    -   F.F.B.E. Bisect.    -   F.F.B.E. Double Bisect.    -   Ring.    -   Dimple.    -   Ellipse.    -   Oval.    -   Capsule.    -   Rectangle.    -   Square.    -   Triangle.    -   Hexagon.    -   Pentagon.    -   Octagon.    -   Diamond.    -   Arrowhead.    -   Bullet.    -   Barrel.    -   Half Moon.    -   Shield.    -   Heart.    -   Almond.    -   House/Home Plate.    -   Parallelogram.    -   Trapezoid.    -   FIG. 8/Bar Bell.    -   Bow Tie.    -   Uneven Triangle.

Core 10 is pressed of a blend of suitable active ingredients andexcipients which may be either their natural color, including white, orcan be conventionally colored as desired to provide a conventional, orelongated-shaped core of any desired color.

The dosage form of the present invention preferably contains one or moreactive ingredients. Suitable active ingredients broadly include, forexample, pharmaceuticals, minerals, vitamins and other nutraceuticals,oral care agents, flavorants and mixtures thereof. Suitablepharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, oral contraceptives, diuretics, expectorants,gastrointestinal agents, migraine preparations, motion sicknessproducts, mucolytics, muscle relaxants, osteoporosis preparations,polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tractagents and mixtures thereof.

Suitable flavorants include menthol, peppermint, mint flavors, fruitflavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueurflavors and combinations and the like.

Examples of suitable gastrointestinal agents include antacids such ascalcium carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminumsodium carbonate; stimulant laxatives, such as bisacodyl, cascarasagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleicacid, and dehydrocholic acid, and mixtures thereof; H2 receptorantagonists, such as famotadine, ranitidine, cimetadine, nizatidine;proton pump inhibitors such as omeprazole or lansoprazole;gastrointestinal cytoprotectives, such as sucraflate and misoprostol;gastrointestinal prokinetics, such as prucalopride, antibiotics for H.pylori, such as clarithromycin, amoxicillin, tetracycline, andmetronidazole; antidiarrheals, such as diphenoxylate and loperamide;glycopyrrolate; antiemetics, such as ondansetron, analgesics, such asmesalamine.

Examples of suitable polydimethylsiloxanes, which include, but are notlimited to dimethicone and simethicone, are those disclosed in U.S. Pat.Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each isexpressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

In one embodiment of the invention, at least one active ingredient maybe selected from bisacodyl, famotadine, ranitidine, cimetidine,prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth,antacids, and pharmaceutically acceptable salts, esters, isomers, andmixtures thereof.

In another embodiment, at least one active ingredient is selected fromanalgesics, anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including a) propionic acidderivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; b)acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac,tolmetin, and the like; c) fenamic acid derivatives, e.g. mefenamicacid, meclofenamic acid, flufenamic acid, and the like; d)biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, andthe like; e) oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam,and the like; f) cyclooxygenase-2 (COX-2) selective NSAIDs; and g)pharmaceutically acceptable salts of the foregoing.

In one particular embodiment, at least one active ingredient is selectedfrom propionic acid derivative NSAID, which are pharmaceuticallyacceptable analgesics/non-steroidal anti-inflammatory drugs having afree —CH(CH₃)COOH or —CH₂CH₂COOH or a pharmaceutically acceptable saltgroup, such as —CH(CH₃)COO—Na+ or CH₂CH₂COO—Na+, which are typicallyattached directly or via a carbonyl functionality to a ring system,preferably an aromatic ring system.

Examples of useful propionic acid derivatives include ibuprofen,naproxen, benoxaprofen, naproxen sodium, fenbufen, flurbiprofen,fenoprofen, fenbuprofen, ketoprofen, indoprofen, pirprofen, carpofen,oxaprofen, pranoprofen, microprofen, tioxaprofen, suprofen,alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, andpharmaceutically acceptable salts, derivatives, and combinationsthereof. In one embodiment of the invention, the propionic acidderivative is selected from ibuprofen, ketoprofen, flubiprofen, andpharmaceutically acceptable salts and combinations thereof. In anotherembodiment, the propionic acid derivative is ibuprofen,2-(4-isobutylphenyl) propionic acid, or a pharmaceutically acceptablesalt thereof, such as the arginine, lysine, or histidine salt ofibuprofen. Other pharmaceutically acceptable salts of ibuprofen aredescribed in U.S. Pat. Nos. 4,279,926, 4,873,231, 5,424,075 and5,510,385, the contents of which are incorporated by reference.

In another particular embodiment of the invention, at least one activeingredient may be an analgesic selected from acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

In another particular embodiment of the invention, at least one activeingredient may be selected from pseudoephedrine, phenylpropanolamine,chlorpheniramine, dextromethorphan, diphenhydramine, astemizole,terfenadine, fexofenadine, loratadine, desloratadine, cetirizine,mixtures thereof and pharmaceutically acceptable salts, esters, isomers,and mixtures thereof.

In another particular embodiment, at least one active ingredient is anNSAID and/or acetaminophen, and pharmaceutically acceptable saltsthereof.

The active ingredient or ingredients are present in the dosage form in atherapeutically effective amount, which is an amount that produces thedesired therapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular active ingredient being administered, the bioavailabilitycharacteristics of the active ingredient, the dosing regimen, the ageand weight of the patient, and other factors must be considered, asknown in the art. Typically, the dosage form comprises at least about 1weight percent, preferably, the dosage form comprises at least about 5weight percent, e.g. about 20 weight percent of a combination of one ormore active ingredients. In one preferred embodiment, the core comprisesa total of at least about 25 weight percent (based on the weight of thecore) of one or more active ingredients.

The active ingredient or ingredients may be present in the dosage formin any form. For example, one or more active ingredients may bedispersed at the molecular level, e.g. melted or dissolved, within thedosage form, or may be in the form of particles, which in turn may becoated or uncoated. If an active ingredient is in form of particles, theparticles (whether coated or uncoated) typically have an averageparticle size of about 1-2000 microns. In one preferred embodiment, suchparticles are crystals having an average particle size of about 1-300microns. In another preferred embodiment, the particles are granules orpellets having an average particle size of about 50-2000 microns,preferably about 50-1000 microns, most preferably about 100-800 microns.

In certain embodiments, at least a portion of one or more activeingredients may be optionally coated with a release modifying coating,as known in the art. This advantageously provides an additional tool formodifying the release profile of active ingredient from the dosage form.For example, the core may contain coated particles of one or more activeingredients, in which the particle coating confers a release modifyingfunction, as is well known in the art. Examples of suitable releasemodifying coatings for particles are described in U.S. Pat. Nos.4,173,626; 4,863,742; 4,980,170; 4,984,240; 5,86,497; 5,912,013;6,270,805; and 6,322,819. Commercially available modified release coatedactive particles may also be employed. Accordingly, all or a portion ofone or more active ingredients in the core may be coated with arelease-modifying material.

In embodiments in which it is desired for at least one active ingredientto be absorbed into the systemic circulation of an animal, the activeingredient or ingredients are preferably capable of dissolution uponcontact with a dissolution medium such as water, gastric fluid,intestinal fluid or the like.

In one embodiment, the dissolution characteristics of at least oneactive ingredient follow an “immediate release profile”. As used herein,an immediate release profile is one in which the active ingredientdissolves without substantial delay or retardation due to the dosageform. This can be contrasted with the dissolution of modified release,e.g. delayed or controlled release dosage forms known in the art. In oneembodiment, the dissolution rate of immediately released activeingredient from the dosage form of the invention is within about 20% ofthe dissolution rate of the active ingredient from a pure crystallinepowder of said active ingredient, e.g. the time for 50%, 75%, 80%, or90% dissolution of active ingredient from the dosage form is not morethan 20% longer than the corresponding time for 50%, 75%, 80%, or 90%dissolution of active ingredient from a pure crystalline powder of saidactive ingredient. In another embodiment, the dissolution of immediatelyreleased active ingredient from the dosage form of the invention meetsUSP specifications for immediate release tablets, gelcaps, or capsulescontaining the active ingredient. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing; and for acetaminophen and codeine phosphate capsules USP24 specifies that at least 75% of the acetaminophen contained in thedosage form is dissolved within 30 minutes in 900 mL of 0.1 NHydrochloric acid using USP Apparatus 2 (paddles) at 50 rpm; and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the dosage form is released therefrom within 60 minutes.See USP 24, 2000 Version, 19-20 and 856 (1999). In yet anotherembodiment, wherein the immediately released active ingredient isacetaminophen, when tested in 37° C. water using USP Apparatus II(paddles) at 50 rpm, at least 80%, preferably at least 85%, of theacetaminophen contained in the dosage form is released therefrom within30 minutes.

In yet another embodiment, the time for release of at least 80%,preferably at least 85%, of at least one active ingredient contained inthe dosage form is released therefrom is not more than about 50%, e.g.not more than about 40% of the time specified by the dissolution methodlisted in the United States New Drug Application for that particularactive ingredient.

In one particularly preferred embodiment, wherein the immediatelyreleased active ingredient is acetaminophen, when tested in 37° C. waterusing USP Apparatus II (paddles) at 50 rpm, at least 80% of theacetaminophen contained in the dosage form is released therefrom withinabout 6 minutes, e.g. within about 5 minutes, or within about 3 minutes.

In another embodiment, the dissolution characteristics of one or moreactive ingredients are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like. In a preferred embodiment inwhich one or more active ingredients are released in a modified manner,the modified release active or actives are preferably contained in thecore. As used herein, the term “modified release” means the release ofan active ingredient from a dosage form or a portion thereof in otherthan an immediate release fashion, i.e., other than immediately uponcontact of the dosage form or portion thereof with a liquid medium. Asknown in the art, types of modified release include delayed orcontrolled. Types of controlled release include prolonged, sustained,extended, retarded, and the like. Modified release profiles thatincorporate a delayed release feature include pulsatile, repeat action,and the like. As is also known in the art, suitable mechanisms forachieving modified release of an active ingredient include diffusion,erosion, surface area control via geometry and/or impermeable orsemi-permeable barriers, and other known mechanisms. General informationon dissolution testing can be found in the United States Pharmacopeiapart <711>. The USP allows for the addition of not more than 3.2 g ofpurified pepsin having an activity of 800 to 2500 units per mg ofprotein, or not more than 5 g of pancreatin per 1000 mL of medium, asappropriate for hard gelatin capsules that do not conform to thedissolution specifications using water or the specified medium forimmediate release tablets.

In certain preferred embodiments, the core 10 is subsequently coveredwith a subcoating 12 that can be any number of medicinally acceptablecoverings. The use of subcoatings is well known in the art and disclosedin, for example, U.S. Pat. No. 5,234,099, which is incorporated byreference herein. Any composition suitable for film-coating a tablet maybe used as a subcoating according to the present invention. Examples ofsuitable subcoatings are disclosed in U.S. Pat. Nos. 4,683,256,4,543,370, 4,643,894, 4,828,841, 4,725,441, 4,802,924, 5,630,871, and6,274,162, which are all incorporated by reference herein. Suitablecompositions for use as subcoatings include those manufactured byColorcon, a division of Berwind Pharmaceutical Services, Inc., 415 MoyerBlvd., West Point, Pa. 19486 under the tradename “OPADRY®” (a dryconcentrate comprising film forming polymer and optionally plasticizer,colorant, and other useful excipients). Additional suitable subcoatingsinclude one or more of the following ingredients: cellulose ethers suchas hydroxypropylmethylcellulose, hydroxypropylcellulose, andhydroxyethylcellulose; polycarbohydrates such as xanthan gum, starch,and maltodextrin; plasticizers including for example, glycerin,polyethylene glycol, propylene glycol, dibutyl sebecate, triethylcitrate, vegetable oils such as castor oil, surfactants such asPolysorbate-80, sodium lauryl sulfate and dioctyl-sodium sulfosuccinate;polycarbohydrates, pigments, and opacifiers.

In one embodiment, the subcoating comprises from about 2 percent toabout 8 percent, e.g. from about 4 percent to about 6 percent of awater-soluble cellulose ether and from about 0.1 percent to about 1percent, castor oil, as disclosed in detail in U.S. Pat. No. 5,658,589,which is incorporated by reference herein. In another embodiment, thesubcoating comprises from about 20 percent to about 50 percent, e.g.,from about 25 percent to about 40 percent of HPMC; from about 45 percentto about 75 percent, e.g., from about 50 percent to about 70 percent ofmaltodextrin; and from about 1 percent to about 10 percent, e.g., fromabout 5 percent to about 10 percent of PEG 400. The dried subcoatingtypically is present in an amount, based upon the dry weight of thecore, from about 0 percent to about 5 percent. The subcoat is typicallyprovided by spraying in a coating pan or fluidized bed to cover thetablet in a conventional manner. The subcoating composition isoptionally tinted or colored with colorants such as pigments, dyes andmixtures thereof.

In one embodiment, subcoating 12 is initially applied to the entireexterior surface of core 10. Subcoating 12 can be applied as a clear,transparent coating such that the core can be seen. The choice isdictated by the preference of the manufacturer and the economics of theproduct. In a preferred embodiment, a commercially available pigment isincluded the subcoating composition in sufficient amounts to provide anopaque film having a visibly distinguishable color relative to the core.

The conventional use of subcoating has been the use of sufficientamounts of subcoating for sufficient weight gain (i.e. the weight of thecoated core is a given % more than the weight of the uncoated core).Conventional gel-dipping processes require sufficient subcoating weightgain to prevent unacceptable bubbling of the dip-coating (referred toherein as the gelatinous coating) and other processing problems. Fordosage forms coated according to the present invention (in which themore than one non-overlapping gelatinous coatings are applied) theamount, as measured by weight gain, of subcoating can be reduced to notmore than about 3%, e.g. not more than about 2.75%, or not more thanabout 2.5%, or not more than about 2.1%, say to about 2% weight gain andstill produce acceptable gelatin coated dosage forms. Weight gaincalculations are well known to those skilled in the art.

FIG. 2 illustrates an intermediate dosage form 20 having two ends 12with gelatinous coatings 24 that do not abut or overlap one another. Thegelatinous coatings 24 are separated from one another and create a gap26. Subsequent to applying subcoating 22 onto core 10, both ends 12 ofcore 10 are covered with gelatinous coatings 24, preferably containing acolorant or coloring agent. The opposing ends 12 of dosage form 20 canbe covered with clear gelatinous materials or gelatinous materialshaving the same color as core 10, the same color as the subcoating 22, adifferent color from the core 10 and/or subcoating 22, and may be thesame or different from one another. Coloring of the gelatinous coating24 may be the result of incorporating a suitable ink, dye or pigmentinto the gelatinous materials. In the preferred embodiment, sufficientpigment is employed to create an opaque colored coating.

In certain preferred embodiments of the invention the dosage formfurther comprises one, or more preferably a plurality of openingsprovided in the exposed portion of the subcoating. The openings may beof any shape and size, and may optionally be arranged in a pattern. Inembodiments in which the openings are made by laser ablation, the widthor diameter of the smallest opening is typically at least 1-2 times thewavelength of light provided by the laser employed. At least a portionof the openings may be large enough to be seen with the unaided humaneye, ranging in width or diameter from about 400 nanometers to as muchas any dimension of the exposed subcoating. Typically, such openingswill have minimum width or diameter of at least about 500 nanometers,e.g. at least about 700 nanometer, or at least about 70 microns.Typically visible openings will have a maximum width or diameter of notmore than the width of the tablet, or not more than the width of theexposed subcoating band, for example not more than about 6.5millimeters, or not more than about 3.5 millimeters, say not more thanabout 2.5 millimeters. Alternatively, some or all of the openings may bemicroscopic in size, ranging from about 1 to less than about 400nanometers in width or diameter. In embodiments in which some or all ofthe openings are invisible to the unaided human eye, a plurality ofopenings may be arranged in a pattern that creates perforations or weakspots in the film, which facilitate disintegration. While it is notcritical to the invention that the initial openings be large enough toallow the influx of water, particularly when water-soluble subcoatingsare employed, it should be noted that it has been found that for certainpreferred embodiments, an opening size of about 0.030 inches in width ordiameter will allow water to pass therethrough.

For purposes of this application, a gelatinous material is defined to bea material that, when applied by dip coating, produces a film coatinghaving a surface gloss comparable to gelatin coatings. “Surface gloss”as used herein, shall refer to amount of light reflectance as measuredat a sixty (60) degree incident angle using the method set forth in theexamples. Preferably, the gelatinous coating has a surface gloss greaterthan about 150, more preferably greater than about 200.

Gelatins have traditionally served as a primary dip-coating material.Hence, the phrase “gelatinous” material. Recently, further work has beendone to expand the range of materials capable of providing the desiredglossy finish that contain substantially no gelatins.

Gelatin is a natural, thermogelling polymer. It is a tasteless andcolorless mixture of derived proteins of the albuminous class, which isordinarily soluble in warm water. Two types of gelatin—Type A and TypeB—are commonly used. Type A gelatin is a derivative of acid-treated rawmaterials. Type B gelatin is a derivative of alkali-treated rawmaterials. The moisture content of gelatin, as well as its Bloomstrength, composition and original gelatin processing conditions,determine its transition temperature between liquid and solid. Bloom isa standard measure of the strength of a gelatin gel, and is roughlycorrelated with molecular weight. Bloom is defined as the weight ingrams required to move a half-inch diameter plastic plunger 4 mm into a6.67% gelatin gel that has been held at 10° C. for 17 hours.

In certain embodiments of the invention, the level of gelatin is fromabout 20% to about 50% by weight of the gelatinous material. In oneparticular such embodiment, the gelatin is a blend of gelatins in whicha first portion has a Bloom value of about 275 and a second portion hasa Bloom value of about 250 Bloom. In certain embodiment the level ofgelatin in the dipping dispersion is from about 25% to about 45%, e.g.about 30 to about 40%, say about 33% by weight of the dippingdispersion. In such embodiments, the level of gelatin is from about 99%to about 99.9% by weight of the finished gelatinous coating.

Suitable water soluble, substantially gelatin-free, film formingcompositions for dip coating tablets or manufacturing capsules via a dipmolding process are described in copending application Ser. No.10/122,999, filed Apr. 12, 2002, published as U.S. 2003-0070584 A1,which is incorporated herein by reference. One such gelatinouscomposition comprises, consists of, and/or consists essentially of afilm former such as a cellulose ether, e.g.,hydroxypropylmethylcellulose; and a thickener, such as a hydrocolloid,e.g., xanthan gum or carrageenan. In another embodiment, the gelatinouscomposition comprises, consists of, and/or consists essentially of afilm former such as a modified starch selected from waxy maize starch,tapioca dextrin, and derivatives and mixtures thereof; a thickenerselected from sucrose, dextrose, fructose, maltodextrin, polydextrose,and derivatives and mixtures thereof; and a plasticizer, e.g.,polyethylene glycol, propylene glycol, vegetable oils such as castoroil, glycerin, and mixtures thereof.

In yet another embodiment, the gelatinous composition comprises,consists of, and/or consists essentially of a film former such as acellulose ether, e.g., hydroxypropyl methylcellulose; and optionally aplasticizer, such as vegetable oils, e.g., castor oil; and mayoptionally be substantially free of thickeners such as hydrocolloids,e.g. xanthan gum. In yet another embodiment, the gelatinous compositioncomprises, consists of, and/or consists essentially of a film formersuch as a cellulose ether, e.g., hydroxypropylmethylcellulose; anextender, such as polycarbohydrates, e.g. maltodextrin; and optionally aplasticizer, such as glycols, e.g., polyethylene glycol; and mayoptionally be substantially free of thickeners such as hydrocolloids,e.g. xanthan gum.

An alternative gelatinous material comprises, consists of, and/orconsists essentially of: a) carrageenan; and b) sucralose, as describedin copending application Ser. No. 10/176,832, filed Jun. 21, 2002,published as U.S. 2003-0108607 A1, which is incorporated herein byreference.

A further alternative gelatinous composition is comprised of, consistingof, and/or consisting essentially of: a) a film former selected from thegroup consisting of waxy maize starch, tapioca dextrin, derivative of awaxy maize starch, derivative of a tapioca dextrin, and mixturesthereof; b) a thickener selected from the group consisting of sucrose,dextrose, fructose, and mixtures thereof; and c) a plasticizer, whereinthe composition possesses a surface gloss of at least 150 when appliedvia dip coating to a substrate.

Another embodiment is directed to a gelatinous composition comprised of,consisting of, and/or consisting essentially of: a) a hydroxypropylstarch film former; b) a thickener selected from the group consisting ofkappa carrageenan, iota carrageenan, maltodextrin, gellan gum, agar,gelling starch, and derivatives and mixtures thereof; and c) aplasticizer, wherein the composition possesses a surface gloss of atleast 150 when applied via dip coating to a substrate. Both embodimentsare described in copending application Ser. No. 10/122,531, filed Apr.15, 2002, published as U.S. 2003-0072731 A1, which is incorporatedherein by reference.

A further gelatinous composition is comprised of, consisting of, and/orconsisting essentially of a film forming composition comprised of,consisting of, and/or consisting essentially of, based upon the totaldry solids weight of the composition: a) from about 10 percent to about70 percent of a film former comprised of a polymer or copolymer of(meth)acrylic acid or a derivative thereof, or a mixture of the polymeror copolymer of (meth)acrylic acid or a derivative thereof; b) fromabout 2 percent to about 20 percent of a primary plasticizer comprisedof a paraben; and c) from about 1 percent to about 50 percent of asecondary plasticizer selected from the group consisting ofpolyvinylpyrrolidone, polyethylene glycol 300, polyethylene glycol 400,pharmaceutically acceptable salts thereof, and mixtures thereof; whereinthe composition possesses a surface gloss of at least 150 gloss unitswhen applied via dip coating to a substrate.

Another embodiment is a gelatinous composition comprised of, consistingof, and/or consisting essentially of, based upon the total dry solidsweight of the composition: a) from about 10 percent to about 70 percentof a film former comprised of a polymer or copolymer of (meth)acrylicacid or a derivative thereof, or a mixture of the polymer or copolymerof (meth)acrylic acid or a derivative thereof; and b) from about 3percent to about 70 percent of a plasticizer selected from the groupconsisting of triacetin, acetylated monoglyceride, rape oil, olive oil,sesame oil, acetyltributyl citrate, glycerin sorbitol, diethyloxalate,diethylmalate, diethyl fumarate, dibutyl succinate, diethylmalonate,dioctylphthalate, dibutylsuccinate, triethylcitrate, tributylcitrate,glyceroltributyrate, propylene glycol, polyethylene glycols,hydrogenated castor oil, fatty acids, substituted triglycerides andglycerides, methyl paraben, ethyl paraben, propyl paraben, butylparaben, polyvinylpyrrolidone, polyethylene glycol 300, polyethyleneglycol 400, and pharmaceutically acceptable salts thereof and mixturesthereof, wherein the composition possesses a surface gloss of at leastabout 150 gloss units when applied via dip coating to a substrate. Eachof the foregoing (meth)acrylic (co)polymer compositions is described incopending application Ser. No. 10/211,139, filed Aug. 2, 2002, which isincorporated herein by reference.

As used herein, “substantially gelatin-free” shall mean less than about1 percent, e.g. less than about 0.5 percent, of gelatin in thecomposition, and “substantially free of thickeners” shall mean less thanabout 1 percent, e.g. less than about 0.01 percent, of thickeners in thecomposition.

One preferred process of manufacturing intermediate dosage form 20begins by compressing or compacting a tablet core 10 into the desiredshape of the medicament. As used herein, “compact, compacting, orcompacted” and “compress, compressing, or compressed” may be usedinterchangeably to describe the commonly used process of compactingpowders into tablets via conventional pharmaceutical tabletingtechnology as well known in the art. One typical such process employs arotary tablet machine, often referred to as a “press” or “compressionmachine”, to compact the powders into tablets between upper and lowerpunches in a shaped die. This process produces a core having two opposedfaces, formed by contact with an upper and lower punch, and having abellyband formed by contact with a die wall. Typically such compressedtablets will have at least one dimension of the major faces at least aslong as the height of the bellyband area between the major faces.Alternately, processes have been disclosed in the prior art to enablethe “longitudinal compression” of tablet cores. When longitudinallycompressed tablets are employed, it has been found that an aspect ratio(height between the major faces to width or diameter of the major faces)from about 1.5 to about 3.5, e.g. about 1.9 facilitates handling.

Tablets are typically compacted to a target weight and “hardness”.Hardness is a term used in the art to describe the diametrical breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across differently sized tablets, the breaking strength isnormalized for the area of the break (which may be approximated astablet diameter times thickness). This normalized value, expressed inkp/cm2, is sometimes referred in the art as “tablet tensile strength.” Ageneral discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329, which is incorporated byreference herein.

Gelatinous coatings 24 are provided by inserting one end 12 of core 10into collets, immersing the exposed end 12 into a selected gelatinousmaterial, and repeating the steps with respect to the opposing end 12 ofcore 10. One method for practicing such a process is described in U.S.Pat. No. 5,234,099, which is incorporated herein by reference. Thegelatinous coatings 24 are provided in such a way that gelatinouscoatings 24 do not meet, and in fact, form a visually discernible gap orband 26 around the non-longitudinal circumference of core 10.Alternatively, when producing a tablet form, the gap would be providedalong and around the bellyband. In the preferred embodiment, subcoating22 is exposed to the environment due to the gap or band region 26.Generally, the minimum attainable gap width is governed by machineprocessing tolerances. The current positioning tolerance forconventional gel-dipping equipment is about +/−0.015 inches. Results ofsensory evaluation indicate that for a dosage form having a length ofabout 0.750 inches and a width of about 0.250 inches, and having the gapat about the midpoint of the long axis of said dosage form, a gap widthrange of about 0.024 to 0.160 inches, e.g. for the gap width range ofabout 0.088 to 0.135 inches, the slipperiness of the dosage form is noteffected, and a majority of panelists cannot detect a height transition,i.e. “step-up” from the subcoating band to the geldipped ends. Incertain embodiments, the width of the gap is from about 3% to about 21%of the length of the uncoated core, which approximates the length of thedosage form.

An alternative means for applying gelatinous coating 24 is by shrinkingwrapping opposing gelatin caps onto the substrate. Shrink wrap processtechnology is known and described in U.S. Pat. Nos. 6,126,767,5,415,868, 5,824,338, 5,089,270, 5,213,738, all assigned to Perrigo andincorporated by reference herein and U.S. Pat. Nos. 5,317,849,5,609,010, 5,460,824, 6,080,426, 6,245,350, 5,464,631, 5,795,588 and5,511,361.

In certain preferred embodiments, intermediate dosage form 20 producedin any of the methods described above is subsequently subjected to amechanical or laser drilling process. A transversely excited atmosphere(TEA) laser is a preferred device for this step, particularly when usedin conjunction with known tablet conveying devices, such as thosecommercially available from Hartnett.

In one embodiment, subcoated and short-dipped gelcaps are fed into aprimary hopper, from which they flow via a chute into the originalhopper of a “Delta” printer, available from R. W. Hartnett Company. Fromthe original hopper, the gelcaps fall in an upright orientation, i.e.the longitudinal axis is oriented vertically, into carrier links, andare conveyed upwards at about a 45-degree angle.

The gelcaps in the carrier links are conveyed between rubber impressionrolls, which can be set at an “open” position, or a “printing” position.The gelcaps in the carrier links are then conveyed through a “drillingsection”, in which a laser beam is rapidly pulsed, as often as every 10microseconds, to coincide with the gelcaps passing therethrough.

The source of the laser beam is an “Impact 2015” Transverse ExcitedAtmosphere CO2 laser available from Lumonics Inc. The laser initiallyemits a 1-inch square beam having 4 Joules of energy towards a turningmirror that redirects the beam 90 degrees (upward) into a series ofturning mirrors and a spherical field lens that reduces the beam from 1inch by 1 inch to about 0.75 inch by 0.75 inch. The focused beamcontinues towards another turning mirror and then passes through astainless steel mask with openings that allows only a portion of thebeam to continue. The actual configuration of series the lenses andmirrors is not essential to the invention and is dictated primarily byspace and cost considerations.

After passing through the mask, the patterned beam is redirected by aseries of turning mirrors into a final focusing lens that reduces thesize of the patterned beam about 5 times. The reduced, patterned beamultimately strikes the gelcaps passing through the “drilling section”,causing the subcoating to be ablated and form shaped openings in apattern determined by the mask. Adjusting the height of the finalturning mirror can modify the striking position of the patterned beam.Mirrors and lenses are commercially available from companies, such asLightMachinery, Inc.

FIG. 3 illustrates final dosage form 30 having ends 12 coated withgelatinous coatings 24 that form a gap 26. Openings 32 are provided ingap 26 that exposes an overcoated exterior surface of core 10. In oneembodiment, the mechanical drill or laser produces at least one,preferably, a plurality of openings or holes 32 entirely throughsubcoating 22 to expose core 10. In another embodiment, the mechanicaldrill or laser produces at least one, preferably a plurality of openings32 through subcoating 22, one gelatinous coating 24, both gelatinouscoatings 24, or combinations thereof. The preferred embodiment providesa plurality of openings 32 only through subcoating 22. In certainoptional embodiments, openings 32 are large enough to be visible to thenaked human eye. In this case, those skilled in the art can appreciatethe advantage of using subcoating 22 and/or gelatinous coating 24 havinga color that is different from that of overcoated core 10 in order tohighlight the presence of openings 32.

The color difference can result from inclusion of a colorant or coloringagent in subcoating 22 and/or gelatinous coating 24. In an alternativeembodiment, the colorant or coloring agent is incorporated intocompacted material used to make core 10, while subcoating 22 and/orgelatinous coatings 24 have one or more different colors from core 10.

A still further embodiment is a final dosage form 30 having openings 32through subcoating 22 and/or one or more gelatinous coatings 24 that arenot visually highlighted. Such an embodiment has subcoating 22 and,optionally, one or more gelatinous coatings 24 that are transparent.Alternatively, subcoating 22 and, optionally, one or more gelatinouscoatings 24 have the same or similar color as overcoated core 10. Anuncolored core 10 has a generally white color, which can be matched bythe use of various white pigments, such as titanium dioxide.Alternatively, core 10 can be modified to include a color other thanwhite, which also can be matched by the colorants or coloring agentsprovided in or over subcoating 22 and/or the gelatinous coatings 24.

An additional embodiment can be a final dosage form 30 that includesprinted material meant to appear as holes or openings 32. Such anembodiment would not exhibit all of the advantages of the presentinvention, though having a visually similar appearance.

Gap or band region 26 can be off-center or centered on final dosage form30. In one embodiment, as to the elongated tablet shaped core 10, gap 26has a width of about 80 to 120 mils. Gap 26 can alternatively beexpressed in terms of the percentage of the length of the elongatedtablet as measured along its longest axis. Gap 26 can be characterizedin such a case as being about 3% to about 33%, e.g. about 3% to about21%, say about 5% to about 15%, the length of the elongated tablet. Asthe gap becomes too small, the level of improved dissolution diminishes,the area for providing openings to the core is reduced, and the visualeffects of the gaps disappear. Additionally, as the gap becomes toolarge, some of the consumer preferences, such as swallowability, for thegelcap dosage forms may be compromised.

The medicaments manufactured according to the present invention,therefore, provide the desired shape, swallowability and appearance fora solid dosage form that substantially eliminates the tamperability ofthe medicament. Further, the discontinuous gel coating and modifiedsubcoating provide improved dissolution and disintegration properties,but surprisingly does not compromise swallowability of the dosage form.

A still further embodiment is a final dosage form 30 having a subcoating22 at a level of not more than about 3.0%, e.g. not more than about2.5%, or not more than about 2.1%, say about 2% relative to the weightof the uncoated core; and/or one or more gelatinous coatings 24 thatform a gap 26, wherein the width of gap 26 is at least about 5% of theoverall length of the uncoated core, and wherein gelatinous coatings 24are substantially free of visible “bubble” defects. A substantiallimitation with previous generations of gel-dipped dosage forms havingoverlapping or abutting gelatinous coatings was the occurrence of bubbledefects. Without wishing to be bound by theory, it is believed that airfrom the compacted core migrated through the subcoating towards thesurface of the dipped gelatinous coating, causing a visible defect.Previous attempts to reduce the subcoating level below about 3.5% basedon the weight of the uncoated compacted core resulted in unacceptablelevels of bubble defects.

It has surprisingly been found that the non-continuous gelatinouscoatings of the present invention enable elegant finished dip-coateddosage forms at subcoating levels less than 3.6%, e.g. not more thanabout 3.0%, or not more than about 2.5%, or not more than about 2.1%,say not more than about 2%, based on the weight of the uncoated core,wherein said dip-coated dosage form is substantially free of visiblebubble defects. As used herein, substantially free of bubble defectsshall mean not more than 4 tablets per hundred, e.g. not more than 1tablet per hundred, say not more than one tablet per thousand, havevisible defects greater than or equal to 2 mm in diameter, and not morethan 13 tablets per hundred, e.g. not more than 3 tablets per hundred,or not more than 1 tablet per hundred, say not more than 2 tablets perthousand have visible defects less than 2 mm in diameter.

It will become apparent to those skilled in the art that variousmodifications to the preferred embodiments of the invention can be madeby those skilled in the art without departing from the spirit or scopeof the invention as defined by the appended claims.

EXAMPLES Example 1 (Comparative) Commercially Available Caplets

Acetaminophen (500 milligrams) film-coated tablets (Extra StrengthTYLENOL® Caplets) are obtained from the manufacturer, McNeil Consumer &Specialty Pharmaceuticals division of McNeil-PPC, Inc. for the purposeof comparative dissolution testing (see Example 7).

Example 2 (Comparative) Preparation of Conventional Gelcaps

2A) Preparation of Uncoated Compacted Cores for Conventional Gelcaps

Compacted cores are prepared in accordance with the procedure set forthin Example 1 of U.S. Pat. No. 5,658,589 (“'589 patent”), which isincorporated by reference herein.

2B) Preparation of Subcoating Dispersion for Conventional Gelcaps

An aqueous dispersion containing the ingredients set forth in Table A isprepared by mixing the HPMC and castor oil into half of the water atslow mixer speed and a temperature 80° C. in a stainless steel jacketedvacuum tank under ambient conditions, then continuing to mix at “fast”speed for 15 minutes. The second half of the water is then added to thetank, with continued mixing at “slow” speed. The solution is thendeaerated by vacuum, and cooled to a temperature of 35° C., withcontinued mixing at “slow” speed. Mixing is then discontinued, vacuumreleased, and the solution is transferred to a pressure pot for sprayingonto the tablet cores.

TABLE A Aqueous Dispersion Subcoating Composition for Comparitor GelcapsIngredient Parts* HPMC (2910, 5 mPs) from Dow Chemical Company 61.2under the tradename, “Methocel E-5” Castor oil 0.24 Water 620.0 TotalCoating Solution 681.44 % solids in coating solution 9% *expressed interms of parts by weight unless otherwise noted2C) Preparation of Subcoated Cores for Conventional Gelcaps

The coating dispersion is then applied onto the compressed tablets viaspraying in accordance with the procedure set forth in the examples ofthe '589 patent. The coating dispersion is applied to the compressedcores in amount sufficient to produce an increased weight of an averageof 4.5% relative to the weight of the subcoating-free compressed cores.

2D) Preparation of Colorless Gelatin-Based Dipping Dispersion

The ingredients in the table below are used to prepare a 1200 literbatch of colorless gelatin-based dipping solution. Purified water at atemperature of about 85° C. is added to a jacketed vacuum-equipped mixtank. Sodium lauryl sulfate (SLS) is added to the water, followed byGelatin 275 Bloom and Gelatin 250 Bloom while mixing. The temperature ofthe mixture after addition of the gelatin blend is approximately 57° C.The gelatin solution is mixed for 10 minutes, and then deaerated undervacuum for 4 hours.

Percent w/w Percent w/w Ingredient of dispersion of gelcap PurifiedWater USP 67.01 — Sodium Lauryl Sulfate 0.03 0.006 Gelatin NF (275 BloomSkin) 10.15 1.8 Gelatin NF (250 Bloom Bone) 22.80 4.22E) Preparation of Yellow Gelatin-Based Dipping Solution

96 kg of colorless gelatin-based dipping solution prepared according toexample 2D is transferred to a jacketed mix tank. 4.30 kg of OpatintYellow DD2125 is added. The solution is mixed at low speed for 4 hours(at ambient pressure) to deaerate while the tank is maintained at asolution temperature of about 55° C.

2F) Preparation of Red Gelatin-Based Dipping Solution

96 kg of colorless gelatin-based dipping solution prepared according toexample 2D is transferred to a jacketed mix tank. 4.30 kg of Opatint RedDD1761 is added. The solution is mixed at low speed for 4 hours (atambient pressure) to deaerate while the tank is maintained at a solutiontemperature of about 55° C.

2G) Geldipping of Subcoated Cores for Conventional Gelcaps

Subcoated cores prepared according to the method of examples 2A-2C,above, are placed (in a plastic tote) at the tablet inlet station of thegeldipping apparatus described in U.S. Pat. No. 5,234,099, which isincorporated herein by reference in its entirety.

Yellow gel-dipping solution prepared according to example 2E herein istransferred to a first gelatin feed tank. Red gel-dipping solutionprepared according to example 2F herein is transferred to a secondgelatin feed tank. Material from each gelatin feed tank is allowed toflow into a separate dip pan. A first end of each subcoated core isdipped into the yellow gel-dipping solution, and a second end of eachsubcoated core is dipped into the red gel-dipping solution, according tothe method and using the apparatus described in U.S. Pat. No. 5,234,099.The gel-dipping operation is carried out using the following operatinglimits:

-   -   Supply air temperature: 26-32° C.    -   Supply air dewpoint: 6-12° C.    -   Supply air volume: 9450-10550 CFM    -   Dip area temperature 15-25° C.    -   Dip area air volume 230-370 CFM    -   Dip pan Temperatures (red and yellow): 44-46° C.    -   Yellow geldipping solution viscosity: 525-675 cps    -   Red geldipping solution viscosity: 675-825 cps    -   Depth of dip to cutline (yellow): 0.406″-0.437″    -   Depth of dip to cutline (red): 0.375″-0.406″    -   Moisture content (% loss on drying at 150° C.) of finished        gelcaps: 2.0-3.0%

Example 3 Preparation of Subcoated Gelcap Cores at 3.0 and 4.5% CoatingLevels

Compressed cores are prepared according to the method set forth inExample 1A herein. 316 kg of the compressed cores are loaded into a48-inch diameter side vented coating pan (Accela Cota) equipped with 4suitable [model JAU available from Spraying Systems Inc.] 2-fluid sprayguns at a gun to tablet bed distance of approximately 12 inches.

An aqueous subcoating dispersion is prepared according to the method ofExample 2B. A 160 kg quantity of subcoating dispersion 2B is meteredinto a pressurized coating dispersion tank equipped with a mixer andvacuum. 1.17 kg of Opatint Red DD1761 is added with mixing at 700 rpmfor 10 minutes. The red subcoating dispersion is deaerated for 10minutes under vacuum.

The red subcoating dispersion is then sprayed onto the compressed coresin an amount (107.4 kg) sufficient to produce an increased weight of anaverage of 3.0% relative to the weight of the uncoated compressed cores.A 20 kg sample of the 3.0% subcoated cores is removed. The 3.0%subcoated cores are referred to herein as sample “3A”. The remainder ofthe panload is then further coated with an additional 53.7 kg ofsubcoating dispersion, to obtain a total increased weight of an averageof 4.5% relative to the weight of the uncoated compressed cores. The4.5% subcoated cores are referred to herein as sample “3B”.

The red subcoating dispersion is mixed at 300 rpm throughout thespraying process. The coating process is conducted, using the followingparameters:

-   -   Coating dispersion tank pressure: 74.0-74.5 PSI    -   Atomizing Air pressure: 71.9-73.9 PSI    -   Dispersion spray rate: 0.63-0.66 kg/minute    -   Supply Air Volumetric Flow Rate: 4190-4319 cubic feet per minute    -   Coating pan pressure: −0.25-−0.30 in. Wc    -   Supply air temperature: 69.3-80.4° C.    -   Exhaust air Temperature: 62.3° C.-64.6° C.    -   Pan speed (first 40 kg of solution): 4.11 rpm    -   Pan speed (after first 40 kg of solution): 6.92 rpm

Example 4 Preparation of Subcoated Gelcap Cores at 2.0% Coating Level

316 kg of compressed cores prepared according to the method set forth inExample 1A herein are loaded into a 48-inch diameter side vented coatingpan (Accela Cota) equipped with 4 suitable [model JAU, available fromSpraying Systems Inc.] 2-fluid spray guns at a gun to tablet beddistance of approximately 12 inches.

An aqueous subcoating dispersion is prepared according to the method ofExample 2B. A 160 kg quantity of subcoating dispersion 2B is meteredinto a pressurized coating dispersion tank equipped with a mixer andvacuum. 2.63 kg of Opatint Red DD1761 is added with mixing at 700 rpmfor 10 minutes. The red subcoating dispersion is deaerated for 10minutes under vacuum.

The red subcoating dispersion is then sprayed onto the compressed coresin an amount (72.2 kg) sufficient to produce an increased weight of anaverage of 2.0% relative to the weight of the uncoated compressed cores.The 2.0% subcoated cores are referred to herein as sample “4”.

The red subcoating dispersion is mixed at 300 rpm throughout thespraying process. The coating process is conducted, using the followingparameters:

-   -   Coating dispersion tank pressure: 75.0 PSI    -   Atomizing Air pressure: 70.2-70.6 PSI    -   Dispersion spray rate: 0.62-0.65 kg/minute    -   Supply Air Volumetric Flow Rate: 4179-4182 cubic feet per minute    -   Coating pan pressure: −0.15-−0.26 in. Wc    -   Supply air temperature: 70.8-81.1° C.    -   Exhaust air Temperature: 61.5° C.-62.7° C.    -   Pan speed (first 40 kg of solution): 3.92 rpm    -   Pan speed (after first 40 kg of solution): 6.82 rpm

Example 5 Geldipping of Subcoated Cores to Prepare the Dosage Form ofthe Invention

5A) 96 kg of colorless gelatin-based dipping solution prepared accordingto example 2D is transferred to a jacketed mix tank. 4.3 kg of OpatintBlue DD-10516 is added. The solution is mixed at low speed for 4 hours(at ambient pressure) to deaerate while heating the tank to maintain asolution temperature of about 55° C.

Blue gel-dipping solution is transferred to a first gelatin feed tank.Blue gel-dipping solution is transferred to a second gelatin feed tank.Material from each gelatin feed tank is allowed to flow into a separatedip pan.

5B) Subcoated cores prepared according to Example 4 (2.0% subcoatinglevel), are transferred to the hopper of the gel-dipping apparatusdescribed in U.S. Pat. No. 5,234,099.

A first end of each subcoated core is dipped into blue gel-dippingsolution, and a second end of each subcoated core is dipped into thesecond blue gel-dipping solution, according to the method and using theapparatus described in U.S. Pat. No. 5,234,099. The gel-dippingoperation is carried out using the following operating limits:

-   -   Supply air temperature: 28° C.    -   Supply air dewpoint: 9° C.    -   Supply air volume: 10013 CFM    -   Dip area temperature 21° C.    -   Dip area air volume 300 CFM    -   Dip pan Temperatures (1^(st) and 2nd): 44.6-44.9° C.    -   Blue (1) gel-dipping solution viscosity: 680 cps    -   Blue (2) gel-dipping solution viscosity: 793 cps    -   Depth of dip to cutline (first blue end): 0.320″-0.333″    -   Depth of dip to cutline (second blue end): 0.320″-0.335″    -   Moisture content (% loss on drying at 150° C.) of finished        gelcaps: 2.0%    -   Gel-dipped coating level (% by weight of subcoated cores): 5.3%

5C) The “short-dipped” gelcaps are then transferred to the hopper of aHartnett Delta Printer equipped with a TEA-Laser, as describedpreviously herein. A plurality of openings is ablated into the exposedsubcoating portion in a pattern, as shown in FIG. 3.

Example 6 Gel-Dipping of Subcoated Cores from Example 3 (4.5% SubcoatingLevel)

6A) Subcoated cores prepared according to example 3 are dipped in bluegel-dipping solution according to the method of Examples 5A&B herein,leaving a band of exposed red subcoating.

6B) A plurality of openings is ablated into the exposed subcoatingportion in a pattern, according to the method of Example 5C herein.

Example 7 Comparative Dissolution Data for 500 mg Acetaminophen SolidDosage Forms

Dissolution testing was performed on various 500 mg acetaminophen soliddosage forms prepared according to the preceding examples (1-6 asindicated in table below). Each test was performed on 6 replicatesamples using a USP Apparatus II (paddles), using a paddle speed of 50rpm, in 900 mL of water at 37 C. Samples were removed at the indicatedtimepoints, filtered, and assayed to determine the concentration ofdissolved acetaminophen. Results are reported in the table below as apercent of theoretical, i.e. 100%=500 mg acetaminophen per 900 mL water.Results reported are the average from 6 vessels at each timepoint.

Time (minutes): 3 6 9 12 15 30 Ex. 1 Caplet 82 97 99 100 100 100 Ex. 2AUncoated Core 81 99 100 101 101 101 Ex, 2C Subcoated Core (4.5%) 4 84 99101 101 102 Ex. 2G Gelcap 0 51 94 99 100 100 Ex. 3B Subcoated Core(4.5%) 17 90 98 99 99 100 Ex. 6A Short dipped from ex. 3B 0 47 91 95 9798 Ex. 6B: 6A with laser openings 63 95 98 99 99 100 Ex. 4 SubcoatedCore (2.0%) 77 96 98 99 99 99 Ex. 5B Short dipped from Ex. 4 40 89 96 9798 99 Ex. 5C: 5B with laser openings 80 95 97 98 98 99

Example 8 Sensory Evaluation of Gap Width

Short-dipped gelcaps prepared according to example 5B, were sortedaccording to the width of the exposed subcoating band, and grouped intothe following categories:

min gap width max gap width Sample (inches) (inches) C 0.08766 0.09766 A0.09846 0.10051 E 0.10110 0.11535 D 0.11206 0.13454 B 0.14008 0.16916One sample from each gap width category was then evaluated by each of 11panelists, and rated according to the following criteria:

-   -   1=Cannot detect a texture difference between exposed subcoating        band and geldipped ends    -   2=some texture difference if scrutinized, but slipperiness of        dosage form not effected, and cannot detect a height transition,        i.e. “step-up” from the subcoating band to the geldipped ends    -   3=definite perceptible texture transition between geldipped ends        and exposed subcoating band    -   4.=can feel a difference in height, i.e. the “step up” from the        subcoating band to the geldipped ends        Results of the evaluation were as follows:

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 avg stdev C 1 1 1 1 1 1 2 2 2 2 21.45 0.52 A 1 1 1 1 1 1 2 2 2 2 1 1.36 0.50 E 1 1 1 1 1 1 2 2 1 2 2 1.360.50 D 1 1 1 1 1 2 2 2 2 1 2 1.45 0.52 B 1 1 1 1 2 2 3 3 2 1 1 1.64 0.81Results of this evaluation indicate that for the gap width range of0.088 to 0.135 inches, the slipperiness of the dosage form is noteffected, and panelists cannot detect a height transition, i.e.“step-up” from the subcoating band to the geldipped ends.

Example 9 Sensory Evaluation of Gap Width

BACKGROUND: Dosage forms of the invention were prepared according to themethod of the present invention. Cores were subcoated, then gel-dipped(“short-dipped”) on each end of the caplet, leaving the subcoatingexposed in the middle section of the long axis if the dosage form. Thedegree of exposed subcoating in the center (gap width) varied among thesix samples from about 0.024 to about 0.160 inches:RESULTS: A texture difference between the subcoated bandwidth andgeldipped ends was not readily detectable among the samples. For all ofthe samples evaluated, 44%-57% of the panelists could not detect atexture difference between the exposed subcoating gap in the middle ofthe gelcap and the geldipped ends.METHODOLOGY: Using a sequential monadic design, subjects were instructedto put a gelcap in their mouth for about 5 seconds and then expectoratethe gelcap. After expectorating the gelcap, panelists were asked toindicate which of four descriptions (see results) best described theiropinion of the texture difference between the subcoating and gelatincoating. The panelists were then instructed to repeat this procedure forfive more samples. The gelcaps were distributed in a random, balancedorder. There were a total of 99 participants from the in-houseacceptance panel in this study.Panelists were asked to indicate, “Which of the following descriptionsbelow best describes your opinion of the gelcap you just had in yourmouth?”

-   -   1. Cannot detect a texture difference between exposed subcoating        band in the middle of the gelcap and the geldipped ends.    -   2. Some texture difference if scrutinized, but slipperiness of        dosage form not effected and cannot detect a height transition,        i.e., “step-up” from the subcoating band in the middle of the        gelcap to the geldipped ends.    -   3. Definite perceptible texture transition between geldipped        ends and exposed subcoating band in the middle of the gelcap.    -   4. Can feel a difference in height, i.e., the “step-up” from the        subcoating band in the middle of the gelcap to the geldipped        ends.

Gap width (inches) (1) (2) (3) (4) Mean* 0.160 53% 29% 14% 4% 1.7 0.14044% 32% 15% 8% 1.9 0.110 51% 26% 16% 7% 1.8 0.060 48% 34% 13% 4% 1.70.040 51% 30% 10% 9% 1.8 0.024 57% 27%  8% 8% 1.7 *An Analysis ofVariance (ANOVA) indicated there were no statistically significantdifferences among the mean scores. Generally, the results of example 9suggest that for the gap width range of 0.024 to 0.160 inches, themajority of panelists could not detect a difference in slipperiness ofthe dosage form, or a height transition, i.e. “step-up” from the gaphaving exposed subcoating to the geldipped ends. To confirmobservational results, a T-test was done to evaluate the differencebetween the 6 totals for the combined response level of scores of 1 and2, and the combined response level for scores 3 and 4. The average ofthe six scores in columns 1 and 2 was 80.333%, with standard deviationof 3.141. The average of the six scores for columns 3 and 4 was 19.333%,with a standard deviation of 3.011. The difference is significant at a plevel of less than 0.0005, which represents a confidence level of100.0%.

Example 10 Surface Gloss Measurement of Coated Tablets

Tablets described below were tested for surface gloss using aninstrument available from TriCor Systems Inc. (Elgin, Ill.) under thetradename, “Tri-Cor Model 805A/806H Surface Analysis System” generallyin accordance with the procedure described in “TriCor Systems WGLOSS 3.4Model 805A/806H Surface Analysis System Reference Manual” (1996), whichis incorporated by reference herein, except as modified below.

The instrument utilized a CCD camera detector, employed a flat diffuselight source, compared tablet samples to a reference standard, anddetermined average gloss values at a sixty (60) degree incident angle.During operation, the instrument generated a gray-scale image, whereinthe occurrence of brighter pixels indicated the presence of more glossat that given location. The instrument also incorporated software thatutilized a grouping method to quantify gloss, i.e., pixels with similarbrightness were grouped together for averaging purposes.

The “percent full scale” or “percent ideal” setting (also referred to asthe “percent sample group” setting), was specified by the user todesignate the portion of the brightest pixels above the threshold thatwill be considered as one group and averaged within that group.“Threshold”, as used herein, is defined as the maximum gloss value thatwill not be included in the average gloss value calculation. Thus, thebackground, or the non-glossy areas of a sample were excluded from theaverage gloss value calculations. The method disclosed in K. Fegley andC. Vesey, “The Effect of Tablet Shape on the Perception of High GlossFilm Coating Systems”, which is available at www.colorcon.com as of 18Mar., 2002 and incorporated by reference herein, was used in order tominimize the effects resulting from different tablet shapes, and thusreport a metric that was comparable across the industry. (Selected the50% sample group setting as the setting which best-approximatedanalogous data from tablet surface roughness measurements.)

After initially calibrating the instrument using a calibration referenceplate (190-228; 294 degree standard; no mask, rotation 0, depth 0), astandard surface gloss measurement was then created using gel-coatedcaplets available from McNeil-PPC, Inc. under the tradename, “ExtraStrength Tylenol Gelcaps.” The average gloss value for a sample of 112of such gel-coated caplets was then determined, while employing the 25mm full view mask (190-280), and configuring the instrument to thefollowing settings:

-   -   Rotation: 0    -   Depth: 0.25 inches    -   Gloss Threshold: 95    -   % Full Scale: 50%    -   Index of Refraction: 1.57        The average surface gloss value for the reference standard was        determined to be 269, using the 50% ideal (50% full scale)        setting. Commercially available gel coated tablets were tested        in accordance with the above procedure. The results are        summarized in table below.

TABLE Gloss values of commercially available coated tablets ExtraExcedrin** Excedrin** Strength Extra Aspirin Excedrin** Migraine TylenolStrength free Migraine Geltab Geltabs* Tylenol Caplets Geltab (white(yellow Geltabs* Product (red) (green side) side) side) (red side) Typeof sprayed gelatin gelatin dipped dipped coating film enrobed enrobedNo. of tablets  40  10  10 112 112 tested Gloss Value 119 270 264 268268 (% ideal at 50) *Available from McNeil-PPC, Inc. **Available fromBristol-Myers, Squibb, Inc.

1. A dosage form comprising: a) a core comprising an exterior surfaceand first and second ends; b) a subcoating over portions of the exteriorsurface of the core; c) a first gelatinous coating over at least a firstpart of the subcoating; and d) a second gelatinous coating over at leasta second part of the subcoating; wherein the first and second gelatinouscoatings are provided on said first and second ends of the core; whereinsaid first and second gelatinous coatings form a gap through which aportion of the subcoating is exposed, and wherein said first and secondgelatinous coatings do not touch or overlap one another; wherein aplurality of openings is provided only through the exposed portion ofthe subcoating; and wherein the subcoating weight gain is less than orequal to about 3%.
 2. A dosage form according to claim 1, whereinsubcoating comprises a polymeric material and does not contain agelatin.
 3. A dosage form according to claim 2, wherein subcoating layerweight gain is less than or equal to about 2.75%.
 4. A dosage formaccording to claim 1, wherein the core is a compressed tablet.
 5. Adosage form according to claim 4, wherein the core has an elongatedshape.
 6. A dosage form comprising: a) a core comprising an exteriorsurface, a subcoating over at least a portion of the exterior surface,first and second ends, and one or more active ingredients; b) a firstgelatinous coating over at least a first part of the core; and c) asecond gelatinous coating over at least a second part of the core;wherein the first and second gelatinous coatings are provided on saidfirst and second ends of the core, and wherein a portion of thesubcoating is not coated with said first or second coatings therebyforming a gap through which the subcoating is exposed; wherein a totalamount of said first and second gelatinous coatings is from about 3 toabout 10 weight percent based on a weight of the core; wherein aplurality of openings is provided only through the exposed portion ofthe subcoating; and wherein the time for release of at least about 80%of the one or more active ingredients, using USP Apparatus II (paddlemethod) at 50 rpm with any dissolution media appropriate for theparticular active ingredient and dosage form, is not more than 50percent of the time specified in the applicable USP or NDAspecifications for immediate release solid dosage forms containing suchactive ingredient.
 7. The dosage form of claim 6, wherein the corecomprises acetaminophen and from which at least about 80% of theacetaminophen is released after 6 minutes in 37° C. water using USPApparatus II (paddle method) at 50 rpm.
 8. The dosage form of claim 6,wherein said first and second gelatinous coatings comprise a gelatin. 9.The dosage form of claim 6, wherein the width of the gap is from about3% to about 21% of the overall length of the uncoated core.
 10. A dosageform comprising: a) a core comprising an exterior surface, a subcoating,and first and second ends; b) a first gelatinous coating over at least afirst part of the core; and c) a second gelatinous coating over at leasta second part of the core; wherein the first and second gelatinouscoatings are provided on said first and second ends of the core, andwherein a portion of the subcoating is not coated with said first orsecond coatings thereby forming a gap through which the subcoating isexposed; wherein total level of said subcoating is not more than about 3weight percent based on a weight of the uncoated core; wherein aplurality of openings is provided only through the exposed portion ofthe subcoating; and wherein said first and second gelatinous coatingsare substantially free of visible bubble defects.
 11. The dosage form ofclaim 10, wherein the width of gap is at least about 5% of the overalllength of the uncoated core.
 12. The dosage form according to claim 1wherein the subcoating contains a coloring agent.
 13. The dosage formaccording to claim 12 wherein the coloring agent is a color other thanthe color of the core.
 14. The dosage form according to claim 6 whereinthe subcoating contains a coloring agent.
 15. The dosage form accordingto claim 14 wherein the coloring agent is a color other than the colorof the core.
 16. The dosage form according to claim 10 wherein thesubcoating contains a coloring agent.
 17. The dosage form according toclaim 16 wherein the coloring agent is a color other than the color ofthe core.
 18. A dosage form according to claim 2, wherein subcoatinglayer weight gain is less than or equal to about 2%.